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INI1/SMARCB1 Rpt1 domain mimics TAR RNA in binding to integrase to facilitate HIV-1 replication

INI1/SMARCB1 binds to HIV-1 integrase (IN) through its Rpt1 domain and exhibits multifaceted role in HIV-1 replication. Determining the NMR structure of INI1-Rpt1 and modeling its interaction with the IN-C-terminal domain (IN-CTD) reveal that INI1-Rpt1/IN-CTD interface residues overlap with those re...

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Autores principales: Dixit, Updesh, Bhutoria, Savita, Wu, Xuhong, Qiu, Liming, Spira, Menachem, Mathew, Sheeba, Harris, Richard, Adams, Lucas J., Cahill, Sean, Pathak, Rajiv, Rajesh Kumar, P., Nguyen, Minh, Acharya, Seetharama A., Brenowitz, Michael, Almo, Steven C., Zou, Xiaoqin, Steven, Alasdair C., Cowburn, David, Girvin, Mark, Kalpana, Ganjam V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115288/
https://www.ncbi.nlm.nih.gov/pubmed/33980829
http://dx.doi.org/10.1038/s41467-021-22733-9
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author Dixit, Updesh
Bhutoria, Savita
Wu, Xuhong
Qiu, Liming
Spira, Menachem
Mathew, Sheeba
Harris, Richard
Adams, Lucas J.
Cahill, Sean
Pathak, Rajiv
Rajesh Kumar, P.
Nguyen, Minh
Acharya, Seetharama A.
Brenowitz, Michael
Almo, Steven C.
Zou, Xiaoqin
Steven, Alasdair C.
Cowburn, David
Girvin, Mark
Kalpana, Ganjam V.
author_facet Dixit, Updesh
Bhutoria, Savita
Wu, Xuhong
Qiu, Liming
Spira, Menachem
Mathew, Sheeba
Harris, Richard
Adams, Lucas J.
Cahill, Sean
Pathak, Rajiv
Rajesh Kumar, P.
Nguyen, Minh
Acharya, Seetharama A.
Brenowitz, Michael
Almo, Steven C.
Zou, Xiaoqin
Steven, Alasdair C.
Cowburn, David
Girvin, Mark
Kalpana, Ganjam V.
author_sort Dixit, Updesh
collection PubMed
description INI1/SMARCB1 binds to HIV-1 integrase (IN) through its Rpt1 domain and exhibits multifaceted role in HIV-1 replication. Determining the NMR structure of INI1-Rpt1 and modeling its interaction with the IN-C-terminal domain (IN-CTD) reveal that INI1-Rpt1/IN-CTD interface residues overlap with those required for IN/RNA interaction. Mutational analyses validate our model and indicate that the same IN residues are involved in both INI1 and RNA binding. INI1-Rpt1 and TAR RNA compete with each other for IN binding with similar IC(50) values. INI1-interaction-defective IN mutant viruses are impaired for incorporation of INI1 into virions and for particle morphogenesis. Computational modeling of IN-CTD/TAR complex indicates that the TAR interface phosphates overlap with negatively charged surface residues of INI1-Rpt1 in three-dimensional space, suggesting that INI1-Rpt1 domain structurally mimics TAR. This possible mimicry between INI1-Rpt1 and TAR explains the mechanism by which INI1/SMARCB1 influences HIV-1 late events and suggests additional strategies to inhibit HIV-1 replication.
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spelling pubmed-81152882021-05-14 INI1/SMARCB1 Rpt1 domain mimics TAR RNA in binding to integrase to facilitate HIV-1 replication Dixit, Updesh Bhutoria, Savita Wu, Xuhong Qiu, Liming Spira, Menachem Mathew, Sheeba Harris, Richard Adams, Lucas J. Cahill, Sean Pathak, Rajiv Rajesh Kumar, P. Nguyen, Minh Acharya, Seetharama A. Brenowitz, Michael Almo, Steven C. Zou, Xiaoqin Steven, Alasdair C. Cowburn, David Girvin, Mark Kalpana, Ganjam V. Nat Commun Article INI1/SMARCB1 binds to HIV-1 integrase (IN) through its Rpt1 domain and exhibits multifaceted role in HIV-1 replication. Determining the NMR structure of INI1-Rpt1 and modeling its interaction with the IN-C-terminal domain (IN-CTD) reveal that INI1-Rpt1/IN-CTD interface residues overlap with those required for IN/RNA interaction. Mutational analyses validate our model and indicate that the same IN residues are involved in both INI1 and RNA binding. INI1-Rpt1 and TAR RNA compete with each other for IN binding with similar IC(50) values. INI1-interaction-defective IN mutant viruses are impaired for incorporation of INI1 into virions and for particle morphogenesis. Computational modeling of IN-CTD/TAR complex indicates that the TAR interface phosphates overlap with negatively charged surface residues of INI1-Rpt1 in three-dimensional space, suggesting that INI1-Rpt1 domain structurally mimics TAR. This possible mimicry between INI1-Rpt1 and TAR explains the mechanism by which INI1/SMARCB1 influences HIV-1 late events and suggests additional strategies to inhibit HIV-1 replication. Nature Publishing Group UK 2021-05-12 /pmc/articles/PMC8115288/ /pubmed/33980829 http://dx.doi.org/10.1038/s41467-021-22733-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Dixit, Updesh
Bhutoria, Savita
Wu, Xuhong
Qiu, Liming
Spira, Menachem
Mathew, Sheeba
Harris, Richard
Adams, Lucas J.
Cahill, Sean
Pathak, Rajiv
Rajesh Kumar, P.
Nguyen, Minh
Acharya, Seetharama A.
Brenowitz, Michael
Almo, Steven C.
Zou, Xiaoqin
Steven, Alasdair C.
Cowburn, David
Girvin, Mark
Kalpana, Ganjam V.
INI1/SMARCB1 Rpt1 domain mimics TAR RNA in binding to integrase to facilitate HIV-1 replication
title INI1/SMARCB1 Rpt1 domain mimics TAR RNA in binding to integrase to facilitate HIV-1 replication
title_full INI1/SMARCB1 Rpt1 domain mimics TAR RNA in binding to integrase to facilitate HIV-1 replication
title_fullStr INI1/SMARCB1 Rpt1 domain mimics TAR RNA in binding to integrase to facilitate HIV-1 replication
title_full_unstemmed INI1/SMARCB1 Rpt1 domain mimics TAR RNA in binding to integrase to facilitate HIV-1 replication
title_short INI1/SMARCB1 Rpt1 domain mimics TAR RNA in binding to integrase to facilitate HIV-1 replication
title_sort ini1/smarcb1 rpt1 domain mimics tar rna in binding to integrase to facilitate hiv-1 replication
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115288/
https://www.ncbi.nlm.nih.gov/pubmed/33980829
http://dx.doi.org/10.1038/s41467-021-22733-9
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